Rifampin-Based Tuberculosis Treatment Versus Rifabutin-Based Tuberculosis Treatment in Persons With HIV
NCT ID: NCT01601626
Last Updated: 2018-02-13
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE2
71 participants
INTERVENTIONAL
2013-07-13
2017-06-28
Brief Summary
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Detailed Description
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At study entry, participants were randomized (1:1:1) to receive standard-dose LPV/r-based HIV treatment plus RBT-based TB treatment (Arm A), double-dose LPV/r-based HIV treatment plus RIF-based TB treatment (Arm B), or standard-dose LPV/r-based HIV treatment plus RAL plus RBT-based TB treatment (Arm C).
Accrual was planned to take place in two accrual periods. Accrual period 1 would enroll 60 participants who would undergo an initial dose-finding period before continuing regular study follow-up. Once the review of the dose-finding pharmacokinetic (PK) and safety data from accrual period 1 participants was completed, accrual period 2 was planned to open to accrual.
Study duration was 72 weeks. Visits occurred at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 72. The key evaluations included physical examination, clinical assessments, TB evaluations including chest x-ray, acid-fast bacilli (AFB) smear, mycobacterial culture, and drug susceptibility testing, CD4 cell count, HIV viral load, hematology, chemistry, and pregnancy testing in women of reproductive potential. Sputum, serum, and urine were stored for use in future analyses. An intensive PK visit occurred at day 12. PK blood draws in participants in Arms A and C were at RBT pre-dose and at 2, 4, 5, 6, and 24 hours RBT post-dose. PK blood draws in participants in Arm B were at LPV/r pre-dose and at 2, 4, 5, and 6 hours LPV/r post-dose.
The target sample size was 471 participants, but the study was terminated after 71 participants due to feasibility concerns. The 71 participants were followed for the planned 72 weeks. Because of the limited sample size, formal statistical comparisons were not undertaken as originally planned.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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A: Standard-dose LPV/r w/RBT
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
Standard-dose Lopinavir/Ritonavir
Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.
Isoniazid
300 mg orally once daily from entry through Week 24.
Pyridoxine
25 mg orally once daily from entry to Week 24.
Pyrazinamide
20 to 30 mg/kg orally once daily (not to exceed 2 g per day) from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
Ethambutol
15 to 20 mg/kg orally once daily from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
Rifabutin
300 mg of rifabutin orally once until LPV/RTV is started; then the dose will be reduced to 150 mg daily from the start of LPV/RTV through Week 24.
B: Double-dose LPV/r w/RIF
ART: lopinavir 800 mg/ritonavir 200 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, weight-based dosing for rifampin, ethambutol, and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
Double-dose Lopinavir/Ritonavir
Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.
Isoniazid
300 mg orally once daily from entry through Week 24.
Pyridoxine
25 mg orally once daily from entry to Week 24.
Pyrazinamide
20 to 30 mg/kg orally once daily (not to exceed 2 g per day) from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
Ethambutol
15 to 20 mg/kg orally once daily from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
Rifampin
Weight-based dose; for weight \< 45 kg: 450 mg orally once daily; for weight \> 45 kg: 600 mg orally once daily, from entry to week 24.
C: Standard-Dose LPV/r w/RBT + RAL
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
Standard-dose Lopinavir/Ritonavir
Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.
Raltegravir
One 400 mg tablet orally twice daily from entry to Week 72.
Isoniazid
300 mg orally once daily from entry through Week 24.
Pyridoxine
25 mg orally once daily from entry to Week 24.
Pyrazinamide
20 to 30 mg/kg orally once daily (not to exceed 2 g per day) from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
Ethambutol
15 to 20 mg/kg orally once daily from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
Rifabutin
300 mg of rifabutin orally once until LPV/RTV is started; then the dose will be reduced to 150 mg daily from the start of LPV/RTV through Week 24.
Interventions
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Standard-dose Lopinavir/Ritonavir
Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.
Double-dose Lopinavir/Ritonavir
Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.
Raltegravir
One 400 mg tablet orally twice daily from entry to Week 72.
Isoniazid
300 mg orally once daily from entry through Week 24.
Pyridoxine
25 mg orally once daily from entry to Week 24.
Pyrazinamide
20 to 30 mg/kg orally once daily (not to exceed 2 g per day) from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
Ethambutol
15 to 20 mg/kg orally once daily from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
Rifabutin
300 mg of rifabutin orally once until LPV/RTV is started; then the dose will be reduced to 150 mg daily from the start of LPV/RTV through Week 24.
Rifampin
Weight-based dose; for weight \< 45 kg: 450 mg orally once daily; for weight \> 45 kg: 600 mg orally once daily, from entry to week 24.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* CD4+/CD8+ T-cell count obtained within 30 days prior to study entry
* Confirmed or probable pulmonary or extrapulmonary TB (more information on the criterion can be found in the protocol)
* Chest x-ray within 30 days prior to study entry
* A PI-based antiretroviral regimen is required, as determined by the participant's primary clinician/clinical facility
* Certain laboratory values obtained within 14 days prior to study entry (more information on the criterion can be found in the protocol)
* For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to study entry and 72 hours of starting study medications
* Willing to use acceptable methods of contraception while on study drugs and for 6 weeks after stopping these drugs
* Karnofsky performance score \> 40 within 14 days prior to study entry, and likelihood of survival, in the opinion of the site investigator, for at least 6 months
* Ability to swallow oral medications
* Ability and willingness of participant or legal guardian/representative to provide informed consent
Exclusion Criteria
* Documented multidrug-resistant tuberculosis (MDR TB) or extensively drug-resistant tuberculosis (XDR TB)
* Participants infected with a rifamycin resistant strain of TB (more information on the criterion can be found in the protocol)
* Receipt of more than 28 cumulative days of anti-TB treatment for the current TB episode prior to study entry
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
* Active illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry, or that in the opinion of the site investigator, might otherwise interfere with adherence to study requirements
* Pregnant or breastfeeding
* Anticipated receipt of prohibited medications (more information on the criterion can be found in the protocol)
* Known intolerance/allergy/sensitivity or any hypersensitivity to components of study drugs or their formulations
* History of close contact with known MDR or XDR TB patients at any time prior to study entry
18 Years
ALL
No
Sponsors
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National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
NETWORK
Responsible Party
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Principal Investigators
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Constance A Benson, MD
Role: STUDY_CHAIR
University of California, San Diego
Umesh Lalloo, MD, FRCP
Role: STUDY_CHAIR
Nelson R. Mandela School of Medicine
Locations
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Hospital Nossa Senhora da Conceicao CRS (12201)
Porto Alegre, Rio Grande do Sul, Brazil
Instituto de Pesquisa Clinica Evandro Chagas (12101)
Rio de Janeiro, , Brazil
Les Centres GHESKIO CRS (30022)
Port-au-Prince, , Haiti
GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)
Port-au-Prince, , Haiti
Moi University Clinical Research Center CRS (12601)
Eldoret, , Kenya
Investigaciones Medicas en Salud (INMENSA) (11302)
San Isidro, Lima region, Peru
Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
Lima, , Peru
Wits HIV CRS (11101)
Johannesburg, Gauteng, South Africa
Durban Adult HIV CRS (11201)
Durban, , South Africa
Countries
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Provided Documents
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Document Type: Statistical Analysis Plan: Primary Analysis
Document Type: Statistical Analysis Plan: PK and Safety Interim Analysis
Document Type: Study Protocol and Informed Consent Form
Related Links
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DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009
Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
Other Identifiers
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ACTG A5290
Identifier Type: -
Identifier Source: org_study_id
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